Process and 5-oxygenated intermediates for the manufacture of 19-norsteroids of the androstane series



United States Patent EROCESS AND S-GXYGENATED MERMEDIATES FOR THE MANUFACTURE 6F 19-NDRSTERGIDS 9F THE ANDROSTANE SERIES Raphael EHEiKl-O, Skokie, ".d Leonard N. Nysted, Highland E m-k, llL, assignors to G. D. Searle & (30., Chicago, Ill., a corporation of Delaware No Drawing. Filed first. 28, 1963, Ser. No. 319,570

Ciaims. (Cl. 260--239.55)

The present invention is concerned with a novel process utilizing novel intermediates in the manufacture of 170: alkynyl-l7fi-hydroxy-l9-norandrost-4-en-3-ones, the latter compounds being represented by the structural formula The aforementioned novel intermediates can be repre sented by the following structural formula i "(lower alkynyl) wherein 'X is either a carbonyl or fl-hydroxymcthylene radical.

Exemplary of the lower ailtynyl radicals encompassed in the foregoing representation are ethynyl, propynyL- corresponding 50:- lower alkano-yl)oxy-6,B-hydroxy compounds, which are allowed to react with a suitable reagent such as lead tetraacetate, lead tetraacetate and iodine, mercuric acetate and iodine, or silver acetate and iodine, resulting in the 65,19-epoxy derivatives. As a specific example, 3,8-acetoxy-5fi,Gfi-epoxyandrostan-17-one is contacted with acetic acid in the presence of p-toluenesulfonic acid at room temperature, and the resulting 3B,

3,l5?,643 Patented Nov. 17, 1964 5a-diacetoxy-dfi-hydroxyandrostan-l7-one in carbon tetrachloride solution is heated with lead tetraacetate and iodine to afford 3fl,5ot-diacetoxy-6,8,l9-epoxyandrostanl7-one. Hydrolysis with potassium carbonate in aqueous methanol yields the desired 6[3,19-epoxy-3B,5a-dihydroxyandrostan-l7-one. When the 17-ketal starting materials are used, that protecting group is removed by reaction With p-toluenesulfonic acid in a suitable organic solvent medium such as acetone.

The novel process of the present invention involves as the first step reaction of 6,8,19-epoxy-3 6,Sm-dihydroXyandrostan-17-one, obtained as described above, with a lower alkyne or with an appropriate organometaliic alkynyl reagent. Examples of suitable reagents are the lithium alkynylides and allrynyl magnesium halides, typically the bromides. When the alkyne itself is used, the process is preferably conducted in the presence of an alkaline catalyst. Specifically illustrative of this alkynylation process is the reaction of the aforementioned starting material With acetylene in the presence of potassium tertiarypentoxide to afford 6,8,19-epoxy-l7ot-ethynylandrostane- 3fi3,5cx,l7,B-triol. Oxidation of that triol, typically with chromic acid in acetone yields 65,19-epoxy-1h-ethynyl- 5a.,l7/i-dihydroxyandrostan-17-one, and reaction of the latter substance with zinc dust and acetic anhydride results in cleavage of the epoxy linkage to afford Net-ethynylandrosta 3,5 diene-3,l7 8,l9 triol 3,17,19-triacetate, That enol ester is hydrolyzed, for example with p-toluenesulfonic acid in methanol, to atiord l7a-ethynyl-l7fi, 19-diacetoxyandrost-4-en-3-one. Removal of the acetate groups can be effected by saponification with potassium hydroxide in aqueous methanol, optionally containing 5,5-dimethylcyclohexanedione-1,3, thus affording 17a-ethynyl-17B-hydroxy-l9-norandrost-4-en-3-one.

As is disclosed in Your aforementioned copending application Serial No. 288,881, the preferred starting material for the instant process, 6fi,l9-epoxy-3fi,5a-dihydroxyandrostan-l7-one, can alternatively be obtained by a procedure involving conversion of the 3-(lower alkanoyl) esters of Sfi,6l3-epoxy 3fi-hydroxyandrostan-17-one to the corresponding Set-(lower alkoxy) derivatives. Typically, 3,8-acetcxy 55,6,8 epoxyandrostan-17-one is contacted with methanol and p-toluenesulfonic acid to afford 3B-acetoxy-6fl-hydroxy-5a methoxyandrostan-l7- one, and the latter substance is converted to the desired 1705-(10V/C1' alkynyl) l7B-hydroxy-l9-norandrost-4-en-3- ones by procedures analogous to those described above involving the related Set-(lower alkanoyl)oxy compounds.

The 17oc-(lOW61 alkynyl)-17B-hydroxy-l9-norandrost-4- en-3-ones produced by the present process utilizing the instantly disclosed novel intermediates are valuable as a result of their pharmacological activity. 17a-ethynyl-lZB- I hydroxy-l9-norandrost-4-en-3-one, for example, is a welllcnown progestational agent.

The invention will appear more fully from the examples which follow. These examples are set forth byway of illustration only, and it will be understood that the invention is not to be construed as limited either in spirit or in scope by the details contained therein as niany modifications in materials and methods will be apparent from this disclosure to those skilled in the art. in these examples, temperatures are given in degrees centigrade C.). Quantities of materials are expressed in parts by weight except where otherwise noted.

Example 2 parts of iodine, and 1600 parts of carbon tetrachloride is stirred and heated at the reflux temperature for about 8 hours. The reaction mixture is cooled, and the insoluble material is removed by filtration. The filtrate is washed with aqueous sodium thiosulfate, then is dried over anhydrous sodium sulfate and concentrated to an oil at reduced pressure. This oil is crystallized from a mixture of methylene chloride and hexane to yield 35,50:- diacetoxy-QB,l9-epoxyaudrostan-l7-one, melting at about 1l2-114.

Example 3 A mixture of 2 parts of 3B,5a-diacetoxy-6{3,19-epoxyandrostan-l7-one, 5 parts of potassium carbonate, 64 parts of methanol, and parts of water is stirred at room temperature for about 60 hours. The organic solvent is removed by distillation at reduced pressure, and approximately parts of Water is added. The resulting solid is collected by filtration, washed on the filter with water, and dried to yield 6fi,l9-epoxy-3fi,5a-dihydroxyandrostan-l7-one, melting at about 270-272".

Example 4 To 101 parts of tertiary-amyl alcohol is added, in a nitrogen atomsphere at the reflux temperature, 10 parts of potassium, and refluxing is continued until solution is complete. This solution is cooled to about 5, and the resulting suspension of potassium tertiary-pentoxide is diluted with an equal volume of ether. Acetylene gas is passed into the mixture for about 30 minutes, after which time 10 parts of 6,8,l9-epoxy-3fl,5a-dihydroxyandrostan-17-one is added. The addition of acetylene is continued for about 3 hours longer, and this reaction mixture is then stored at 0-5 for about 16 hours. To that mixture is added approximately 100 parts of 10% aqueous ammonium chloride, and the tertiary-amyl alcohol is removed by steam-distillation. The solid which separates is collected by filtration, washed with water, and dried. Recrystallization from methanol-ethyl acetate produces pure 6,8,l9-epoxy-l7a-ethynylandrostane- 3/3,5oc,l7}3-tfi0l, melting at about 285-287. It is represented by the structural formula -czon on? Example 5 removed by distillation at reduced pressure. The result ing mixture is diluted with water, and the solid material is collected by filtration, then washed and dried. Recrystallization from a mixture of tetrahydrofuran and ethyl acetate results in pure 6,6,19-epoxy-l7u-ethynyl- 5d,175-dihydroxyandrostan-3-one, melting at about 295- 300 and represented by the structural formula Example 6 A mixture of 1.08 parts of 6fi,l9-epoxy-l7a-ethynyl- 5a,l7 3-dihydroxyandrostan-3-one, 10 parts of zinc dust, and 54 parts of acetic anhydride is heated at the reflux temperature in an atmosphere of nitrogen for about 3 hours. This reaction mixture is then cooled, filtered, and concentrated to dryness under reduced pressure to yield 170: ethynylandrosta 3,5 dicne 3,l7 8,l9 triol 3,17,19-triacetate.

To a solution of 5.4 parts of l7a-ethynylandrosta-3,5- diene-3,17,8,l9-triol 3,17,19-triacetate in parts of methanol is added 5 parts of p-toluenesulfonic acid, and the resulting mixture is kept at room temperature for about 16 hours. Removal of the solvent by distillation at reduced pressure affords a residue which is extracted with benzene. The benzene solution is washed successively with aqueous sodium bicarbonate and Water, then is concentrated to dryness at reduced pressure to afford 17aethynyl-17,8, l9-diacetoxyandrost-4-en-3-one.

Example 7 To a solution of 1.17 parts of l7a-ethynylandrosta- 3,5-diene-3,l7;3,l9-triol 3,17,19-triacetate in parts of ethanol is added a solution of 2 parts of 5,5-dirnethylcyclohexanedione-l,3 in 100 parts by volume of 3.4 N aqueous potassium hydroxide. This reaction mixture is stored at room temperature for about 6 hours, then is diluted with water and extracted with benzene. The organic solution is washed successively with 10% aqueous potassium hydroxide and water, dried over anhydrous sodium sulfate, and concentrated to dryness, resulting in 17a-ethynyl-17fi-hydroxy-19-norandrost-4-en-one.

Example 8 A mixture of 10.9 parts of 17a-ethynyl-17fi,19-diacetoxyandrost-4-en-3-one, 500 parts by volume of 3.4 N potassium hydroxide, and 80 parts of ethanol is stored at room temperature for about 3 hours, then is concentrated to dryness at reduced pressure. The resulting residue is extracted with benzene, and the benzene solution is washed successively with dilute hydrochloric acid and water. Drying over anhydrous sodium sulfate followed by distillation of the solvent at reduced pressure yields 17a-ethynyl-l7B-hydroxy-19-norandrost-4-en-3-one, identical with the product of Example 7.

Example 9 To a mixture of 0.08 part of p-toluenesulfonic acid in 16 parts of methanol is added 10 parts of BfJ-acetoxy- 53,6,8-epoxyandrostan-l7-one, and this reaction mixture is stirred at room temperature for about 15 minutes. At the end of this time, an additional 0.08 part of p-toluenesulfonic acid and approximately 3 parts of methanol are added, and stirring is continued for about 15 minutes longer in order to achieve complete solution. The reaction mixture is diluted with water and extracted I 5 with ethyl acetate. The ethyl acetate layer is separated, washed with dilute aqueous potassium bicarbonate, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to afford a crystalline residue. Recrystallization from a mixture of methylene chloride, hexane, and ether yields pure 3,8-acetoxy-6fi-hydroxy- Sa-methoxyandrostan-17-one, melting at about 201-203".

What is claimed is:

1. A process for the manufacture of 17a-ethynyl-17flhydroxy-19-n0randrost-4-en-3-one which comprises the steps of contacting ofi,l9-epoxy-3B,Sa-dihydroxyandmstan-17-one with acetylene, oxidizing the resulting 65,19- epoxy-17a-etl1ynylandrostane-3fi,5a,17,8-triol with chromium trioxide to afford 65,19-epoxy-17a-ethyny1-5a,17,6- dihydroxyandrostan-3-one, contacting the latter substance with zinc and acetic anhydride to yield 17a-ethynylandrosta-3 ,5-diene-3,17B,19-triol 3,17,l'9-triacetate, hydrolyzing that triester with p-toluenesulfonic acid to produce l7m-etl1yny1-17B,19-diacetoXyandrost-4-en-3-one, and contacting the latter compound With an alkali metal hydroxide, resulting in l7a-ethynyl-17 8-hydroxy-l9-norandrost- 4-en-3-one.

2. A process for the manufacture of 17a-ethynyl-17flhydroxy-19-norandrost-4-en-3-one which comprises the steps of contacting 6,8,19-epoxy-3{3,5a-dihydroXyandrostan-17-one with acetylene, oxidizing the resulting 66,19- epox '-17a-ethynylandrostane-3B,5a,17B-triol With chrmium trioxide to afford 6e,19-epoxy-l7a-ethynyl-5a,17pdihydroxyandrostan-3-one, contacting the latter substance 5 with zinc and acetic anhydride to yield 17a-ethynylandrosta-3 ,5 -diene-3, 17B, 1 9-triol 3,17,19-triacetate, and contacting that triester With an alkali metal hydroxide in the presence of 5,5-dimethylcyclohexanedione-1,3 to yield l'l'a-ethynyl-flfi-hydroxy-19-norandrost-4-en-3-one.

3. A compound of the formula L-CECH CHzfi i X 0 i\ 011 wherein X is selected from the group of radicals consisting of carbonyl and fl-hydroxymethylene.

4. 65,19-epoxy-17a-ethynylandrostane-3fl,5a,17,6-triol. 5 6,8,19-epoxy-17m-ethynyl-5a,17fl-dihydroxyandrostan- 3-one.

Berkoz et al.: Steroids, vol. 1, No. 3, March 1963, pp. 251-370. 

3. A COMPOUND OF THE FORMULA 